Method for producing bicyclic compound

ABSTRACT

A method for producing a compound, such as 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate, and a novel intermediate suitable for the method, whereby the compound can be stably supplied with a high total reaction yield, by changing the starting material and improving the metathesis reaction, asymmetric reduction reaction and the like.

TECHNICAL FIELD

The present invention relates to a method for producing a bicycliccompound represented by the following general formula (K), which isuseful as an intermediate for the manufacture of a medicine or as a drugsubstance for a medicine. Among others, the present invention relates toa method for producing 2-propanyl4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate(hereinafter sometimes abbreviated as the present compound), which canprovide the same even on an industrial production scale in a goodreaction yield.

BACKGROUND ART

The bicyclic compound which can be produced by the present invention hasan FP agonist activity and is known as a medicine useful as aprophylactic and/or therapeutic agent for ocular diseases and the like(see Patent Literature 1). Among others, 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoateis known as Sepetaprost (International Nonproprietary Name) and thedevelopment as a therapeutic agent for glaucoma is underway.

Various production methods have been examined in providing the presentcompound as a drug substance for a medicine. For example, a method forproducing the present compound (hereinafter sometimes abbreviated as aknown production method) described in Example 16 (25) described inPatent Literature 1 is known. However, the known production method hasthe following three problems. That is, it has turned out that there havebeen problems such as: (1) the total number of steps is as large as 16steps; (2) the yield by a metathesis reaction is low; and (3) the yieldof a desired diastereomer is low in an asymmetric reduction reaction.Due to such problems in the known production method, it has beenconsidered that the total reaction yield is low and the synthesis costbecomes high in manufacturing the present compound on an industrialproduction scale. Therefore, there has been a demand for a method forproducing the present compound which solves the problems of the knownproduction method, which is suitable for an industrial production scale,which has a high total reaction yield and which can stably supply thepresent compound.

CITATIONS LIST Patent Literature

-   Patent Literature 1: WO 2011/013651 A

SUMMARY OF INVENTION Technical Problems

An object of the present invention is to provide a method for producinga compound represented by the general formula (K), particularly a methodfor producing the present compound, which solves various problems of theknown production method and is suitable for an industrial productionscale, and a novel intermediate suitable for the production method.

Solutions to Problems

As a result of intensive studies to solve the above-described problems,the present inventors have found a method for producing a compoundrepresented by the general formula (K) which surprisingly solves theseproblems by changing the starting material, and improving the metathesisreaction, asymmetric reduction reaction, and the like, and havecompleted the present invention.

That is, the present invention relates to:

[1] A method for producing a compound represented by the general formula(K):

wherein, Y represents —CH₂—, —O— or —S—, ring 1 represents a C3-10carbocycle or a 3- to 10-membered heterocycle optionally substitutedwith 1 to 5 substituents selected from the group consisting of (1) ahalogen atom, (2) CF₃, (3) OCF₃, (4) a C1-4 alkoxy group, (5) a C1-4alkyl group, (6) a hydroxyl group, and (7) a nitrile group, R¹represents a C1-6 alkyl group optionally substituted with a hydroxylgroup or a C1-4 alkoxy group, Z represents (1) —(CH₂)_(m)—, (2)—(CH₂)_(n)—CH═CH—, or (3) —(CH₂)_(p)-A-CH₂—, A represents an oxygenatom, or a sulfur atom, m represents an integer of 1 to 6, n representsan integer of 1 to 4, and p represents an integer of 1 to 4,

the method comprising:

step (x): subjecting a compound represented by the general formula (J):

wherein, T¹ represents (1) a p-phenybenzoyl group, (2) a methyl group,(3) a trityl group, (4) a methoxymethyl group, (5) a 1-ethoxyethylgroup, (6) a methoxyethoxymethyl group, (7) a benzyloxymethyl group, (8)a trimethylsilyl group, (9) a triethylsilyl group, (10) at-butyldimethylsilyl group, (11) a t-butyldiphenylsilyl group, (12) atriisopropylsilyl group, (13) a benzyl group, (14) a p-methoxybenzylgroup, (15) an acetyl group, (16) a pivaloyl group, (17) a benzoylgroup, (18) an allyloxycarbonyl group, (19) a2,2,2-trichloroethoxycarbonyl group, (20) a t-butoxycarbonyl group, (21)an allyl group, or (22) a tosyl group, and other symbols represent thesame meanings as those described above, or a salt thereof to adeprotection reaction to produce the compound represented by the generalformula (K);

[2] A method for producing the compound represented by the generalformula (K) described in the above [1]:

wherein, all symbols represent the same meanings as those describedabove,

the method comprising the following steps (ix) to (x):

step (ix): subjecting a compound represented by the general formula (I):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof to an asymmetric reduction reaction to producethe compound represented by the general formula (J) described in theabove [1] or a salt thereof; and

step (x): subjecting the compound represented by the general formula (J)described in the above [1] or a salt thereof to a deprotection reactionto produce the compound represented by the general formula (K);

[3] A method for producing the compound represented by the generalformula (I) described in the above [2] or a salt thereof, the methodcomprising the following steps (vii) to (viii):

step (vii): subjecting a compound represented by the general formula(G):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof to an oxidation reaction to produce a compoundrepresented by the general formula (H):

wherein, all symbols represent the same meanings as those describedabove; and

step (viii): subjecting the compound represented by the general formula(H) obtained in the step (vii) and a compound represented by the generalformula (b):

wherein, R¹⁰¹ represents a C1-6 alkyl group, and other symbols representthe same meanings as those described above,

to a reaction in an organic solvent, in water, or in a mixed solutionthereof, in the presence of a base, in the presence or absence of anadditive to produce the compound represented by the general formula (I)described in the above [2] or a salt thereof;

[4] A method for producing the compound represented by the generalformula (G) described in the above [3] or a salt thereof, the methodcomprising the following steps (i) to (vi):

step (i): subjecting a compound represented by the general formula (A):

wherein, T² represents (1) a p-phenybenzoyl group, (2) a methyl group,(3) a trityl group, (4) a methoxymethyl group, (5) a 1-ethoxyethylgroup, (6) a methoxyethoxymethyl group, (7) a benzyloxymethyl group, (8)a trimethylsilyl group, (9) a triethylsilyl group, (10) atetrahydropyranyl group, (11) a t-butyldiphenylsilyl group, (12) atriisopropylsilyl group, (13) a benzyl group, (14) a p-methoxybenzylgroup, (15) an acetyl group, (16) a pivaloyl group, (17) a benzoylgroup, (18) an allyloxycarbonyl group, (19) a2,2,2-trichloroethoxycarbonyl group, (20) a t-butoxycarbonyl group, (21)an allyl group, or (22) a tosyl group, and other symbols represent thesame meanings as those described above, to a reduction reaction toproduce a compound represented by the general formula (B):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof;

step (ii): subjecting the compound represented by the general formula(B) obtained in the step (i) or a salt thereof to a reaction in anorganic solvent, in the presence of a base with using a Wittig reagentto produce a compound represented by the general formula (C):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof;

step (iii): subjecting the compound represented by the general formula(C) obtained in the step (ii) or a salt thereof and a compoundrepresented by the general formula (a):

wherein, X represents a halogen atom, a tosyloxy (TsO) group, or amesyloxy (MsO) group, and other symbols represent the same meanings asthose described above, to an alkylation reaction to produce a compoundrepresented by the general formula (D):

wherein, all symbols represent the same meanings as those describedabove;

step (iv): subjecting the compound represented by the general formula(D) obtained in the step (iii) to a metathesis reaction to produce acompound represented by the general formula (E):

wherein, all symbols represent the same meanings as those describedabove;

step (v): subjecting the compound represented by the general formula (E)obtained in the step (iv) to an asymmetric reduction reaction to producea compound represented by the general formula (F):

wherein, all symbols represent the same meanings as those describedabove; and

step (vi): subjecting the compound represented by the general formula(F) obtained in the step (v) to a deprotection reaction to produce thecompound represented by the general formula (G) described in the above[3] or a salt thereof;

[5] A method for producing the compound represented by the generalformula (K) described in the above [1], the method comprising: producingthe compound represented by the general formula (G) or a salt thereoffrom the compound represented by the general formula (A) according tothe steps (i) to (vi) described in the above [4]; producing the compoundrepresented by the general formula (I) or a salt thereof from thecompound represented by the general formula (G) or a salt thereofaccording to the steps (vii) to (viii) described in the above [3]; andproducing the compound represented by the general formula (K) accordingto the steps (ix) to (x) described the above [2];[6] The method according to any one of the above [1] to [5], wherein T¹is a p-phenybenzoyl group;[7] The method according to any one of the above [4] to [6], wherein T²is a benzyl group;[8] The method according to any one of the above [1], [2], [5], [6], and[7], wherein the compound represented by the general formula (K) is2-propanyl4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate;[9] (3aR,4S,5R,6aS)-4-[(benzyloxy)methyl]-2-hydroxyhexahydro-2H-cyclopenta[b]furan-5-yl4-biphenylcarboxylate;[10] (1R,2S,3R,4S)-3-allyl-2-[(benzyloxy)methyl]-4-hydroxycyclopentyl4-biphenylcarboxylate;[11] 2-propanyl 5-(bromomethyl)-5-hexenoate;[12](1R,2S,3R,4S)-3-allyl-2-[(benzyloxy)methyl]-4-{[2-methylene-6-oxo-6-(2-propanyloxy)hexyl]oxy}cyclopentyl4-biphenylcarboxylate;[13](5aR,6S,7R,8aS)-6-[(benzyloxy)methyl]-3-[4-oxo-4-(2-propanyloxy)butyl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate;[14](3S,5aR,6S,7R,8aS)-6-[(benzyloxy)methyl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate;[15] (3S,5aR,6R,7R,8aS)-6-[(1E)-4-(2,5-difluorophenoxy)-3-oxo-1-buten-1-yl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate; and[16](3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate;and the like.

Advantageous Effects of Invention

According to the present invention, by changing the starting materialand improving the metathesis reaction, the asymmetric reduction reactionand the like, the total number of steps can be reduced, the totalreaction yield can be high, and the present compound can be stablysupplied, and therefore, the present invention is an extremely usefulproduction method from the viewpoint of industrial productivity of thepresent compound which is a drug substance for a medicine.

DESCRIPTION OF EMBODIMENTS

Hereinafter, the present invention will be described in detail.

In the present invention, the C1-6 alkyl group means a straight orbranched C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl,and hexyl.

In the present invention, the C1-4 alkyl group means a straight orbranched C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, and tert-butyl.

In the present invention, the C1-4 alkoxy group means a straight orbranched C1-4 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutyloxy, and tert-butoxy.

In the present invention, the halogen atom means fluorine, chlorine,bromine, and iodine.

In the present invention, the C3-10 carbocycle means a C3-10 monocyclicor bicyclic carbocycle, a part or all of which may be saturated, andexamples include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene,cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene,azulene, perhydroazulene, indene, perhydroindene, indane,perhydroindane, naphthalene, dihydronaphthalene, tetrahydronaphthalene,perhydronaphthalene and the like.

In the present invention, the C3-7 carbocycle means a C3-7 monocycliccarbocycle, a part or all of which may be saturated, and examplesinclude cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene,cyclohexadiene, cycloheptadiene, benzene and the like.

In the present invention, the 3- to 10-membered heterocycle means a 3-to 10-membered monocyclic or bicyclic heterocycle, a part or all ofwhich may be saturated, comprising 1 to 5 heteroatoms selected from anoxygen atom, a nitrogen atom and a sulfur atom, and examples includepyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin,thiophene, thiopyran, thiepin, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, aziridine, azetidine, pyrroline, pyrrolidine,imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline,tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin,tetrahydrooxepin, perhydrooxepin, thiirane, thietane, dihydrothiophene,tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran,dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, dioxolane,dioxane, dithiolane, dithiane, indole, isoindole, indolizine,benzofuran, isobenzofuran, benzothiophene, isobenzothiophene,dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine,purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline,cinnoline, pyrrolopyridine, benzoxazole, benzothiazole, benzimidazole,chromene, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,tetrahydropyrrolopyridine, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, benzoxathian, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, and perhydrobenzimidazole.

In the present invention, the sulfur atom in A includes an oxidizedsulfur atom, that is, —SO— or —SO₂— in addition to —S—.

In the present invention, the present compound means the compoundrepresented by the following formula:

that is, 2-propanyl4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate.

In the present invention, the step (i) means a step of subjecting acompound represented by the general formula (A):

wherein, all symbols represent the same meanings as those describedabove, to a reduction reaction to produce a compound represented by thegeneral formula (B):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof.

The reduction reaction in the step (i) can be carried out, for example,in an organic solvent (for example, toluene, ethanol, tetrahydrofuran,hexane, methylene chloride and the like), in the presence of a reducingagent (for example, diisobutylaluminium hydride (DIBAL), lithiumaluminium hydride, sodium borohydride and the like) at −78 to 80° C.Here, the organic solvent is preferably tetrahydrofuran, and thereducing agent is preferably DIBAL.

In the present invention, the step (ii) means a step of subjecting acompound represented by the general formula (B) obtained in the step (i)or a salt thereof to a reaction in an organic solvent, in the presenceof a base, by using a Wittig reagent to produce a compound representedby the general formula (C):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof.

Examples of the organic solvent in the step (ii) include anhydroustoluene, dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like,with tetrahydrofuran being preferred.

Examples of the base in the step (ii) include lithiumhexamethyldisilazane (LHMDS), lithium diisopropylamide (LDA),butyllithium, potassium tert-butoxide, sodium hydride and the like, withpotassium tert-butoxide being preferred.

Examples of the Wittig reagent in the step (ii) includemethyltriphenylphosphonium bromide and the like.

In the present invention, the step (iii) means a step of subjecting acompound represented by the general formula (C) obtained in the step(ii), or a salt thereof and a compound represented by the generalformula (a):

wherein, all symbols represent the same meanings as those describedabove, to an alkylation reaction to produce a compound represented bythe general formula (D):

wherein, all symbols represent the same meanings as those describedabove.

The alkylation reaction in the step (iii) is known, and can be carriedout, for example, by using a compound represented by the general formula(C) or a salt thereof and a compound represented by the general formula(a) in an organic solvent (for example,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),N-methylpyrrolidone (NMP), hexamethylphosphoric triamide,dimethylformamide and the like), in the presence of a base (for example,sodium tert-butoxide, sodium hydride, lithium diisopropylamide (LDA),sodium hexamethyldisilazane and the like) at −78 to 80° C. Here, DMPU ispreferably used as the organic solvent, and sodium tert-butoxide ispreferably used as the base.

In the present invention, the step (iv) means a step of subjecting acompound represented by the general formula (D) obtained in the step(iii) to a metathesis reaction to produce a compound represented by thegeneral formula (E):

wherein, all symbols represent the same meanings as those describedabove.

The metathesis reaction in the step (iv) is known and can be carriedout, for example, by using a metathesis catalyst (for example,2,6-diisopropylphenylimido neophylidenemolybdenum(VI)bis(tert-butoxide), 2,6-diisopropylphenylimidoneophylidenemolybdenum(VI) bis(hexafluoro-tert-butoxide), Umicore M2(trade name) and the like) in an organic solvent (for example, toluene,methylene chloride, dichloroethane and the like) at a temperature of 20to 110° C. Here, the organic solvent is preferably toluene, and themetathesis catalyst is preferably Umicore M2.

In the present invention, the step (v) means a step of subjecting acompound represented by the general formula (E) obtained in the step(iv) to an asymmetric reduction reaction to produce a compoundrepresented by the general formula (F):

wherein, all symbols represent the same meanings as those describedabove.

The asymmetric reduction reaction in the step (v) is known, and can becarried out, for example, by using an iridium catalyst (for example,bis(cyclooctadiene)iridium(I)tetrakis[3,5-bis(trifluoromethyl)phenyl]borate and the like) and aligand (for example,(S,S)-(4,5-dihydro-4-isopropyl-2-oxazolyl)-2-[di(1-naphthyl)phosphino]ferroceneand the like) in an organic solvent (for example, methylene chloride,dichloroethane, tetrahydrofuran, methanol and the like) at a temperatureof 20 to 80° C. Here, the organic solvent is preferably methylenechloride, and preferable examples of the combination of the iridiumcatalyst and the ligand include a combination oftetrakis[3,5-bis(trifluoromethyl)phenyl]borate and(S,S)-(4,5-dihydro-4-isopropyl-2-oxazolyl)-2-[di(1-naphthyl)phosphino]ferrocene.

In the present invention, the step (vi) means a step of subjecting acompound represented by the general formula (F) obtained in the step (v)to a deprotection reaction to produce a compound represented by thegeneral formula (G):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof.

In the step (vi), a deprotection reaction of a hydroxyl group is known,and examples include:

(1) a deprotection reaction under the basic condition,

(2) a deprotection reaction under the acidic condition,

(3) a deprotection reaction by hydrogenation degradation,

(4) a deprotection reaction of a silyl group,

(5) a deprotection reaction using a metal,

(6) a deprotection reaction using a metal complex, and the like.

To specifically describe these methods,

(1) The deprotection reaction under the basic condition is performed,for example, by using, a hydroxide of an alkali metal (sodium hydroxide,potassium hydroxide, lithium hydroxide and the like), a hydroxide of analkaline earth metal (barium hydroxide, calcium hydroxide and the like),an alkoxide of an alkali metal (sodium methoxide, sodium ethoxide,lithium isopropoxide and the like), or a carbonate (sodium carbonate,potassium carbonate and the like), or an aqueous solution thereof, or amixture thereof, in an organic solvent (methanol, ethanol, isopropanol,tetrahydrofuran, dioxane and the like) at a temperature of 0 to 80° C.

(2) The deprotection reaction under the acidic condition is performed,for example, in an organic solvent (dichloromethane, chloroform,dioxane, ethyl acetate, anisole and the like), in an organic acid(acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosic acidand the like), or an inorganic acid (hydrochloric acid, sulfuric acidand the like) or a mixture thereof (hydrogen bromide/acetic acid and thelike) at a temperature of 0 to 100° C.

(3) The deprotection reaction by hydrogenation degradation is performed,for example, in a solvent (for example, ether-based solvent (forexample, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether andthe like), alcohol-based solvent (for example, methanol, ethanol and thelike), benzene-based solvent (for example, benzene, toluene and thelike), ketone-based solvent (for example, acetone, methyl ethyl ketoneand the like), nitrile-based solvent (for example, acetonitrile and thelike), amide-based solvent (for example, N,N-dimethylformamide and thelike), water, ethyl acetate, isopropyl acetate, acetic acid or a mixedsolvent of two or more of them and the like), in the presence of acatalyst (for example, palladium on carbon, palladium black, palladiumhydroxide on carbon, platinum oxide, Raney nickel and the like), underthe hydrogen atmosphere at a normal pressure or under pressure, or inthe presence of ammonium formate, at 0 to 200° C.

(4) The deprotection reaction of a silyl group is performed, forexample, in an organic solvent which is miscible with water(tetrahydrofuran, acetonitrile and the like), by usingtetrabutylammonium fluoride, at a temperature of 0 to 40° C.

(5) The deprotection reaction by using a metal is performed, forexample, in an acidic solvent (acetic acid, a buffer of pH 4.2 to 7.2,or a mixed solution of any of those solutions and an organic solventsuch as tetrahydrofuran), in the presence of a zinc powder, ifnecessary, while an ultrasound is applied, at a temperature of 0 to 40°C.

(6) The deprotection reaction by using a metal complex is performed, forexample, in an organic solvent (dichloromethane, dimethylformamide,tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol and thelike), water or a mixed solvent thereof, in the presence of a trapreagent (tributyltin hydride, triethylsilane, dimedone, morpholine,diethylamine, pyrrolidine and the like), an organic acid (acetic acid,formic acid, 2-ethyhexanoic acid and the like) and/or an organic acidsalt (sodium 2-ethylhexanoate, potassium 2-ethylhexanoate and the like),in the presence or absence of a phosphine-based reagent(triphenylphosphine and the like), by using a metal complex(tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate,chlorotris(triphenylphosphine)rhodium(I) and the like) at a temperatureof 0 to 40° C.

In the step (vi), when T² is a benzyl group, it is preferable to useisopropyl acetate as a solvent, and palladium on carbon as a catalyst,and to perform the deprotection reaction under the hydrogen atmosphereunder pressure.

Additionally, in addition to the above reactions, the deprotectionreaction can be performed, for example, by the method described in T. W.Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.

In the present invention, the step (vii) means a step of subjecting acompound represented by the general formula (G) obtained in the step(vi), or a salt thereof to an oxidation reaction to produce a compoundrepresented by the general formula (H):

wherein, all symbols represent the same meanings as those describedabove.

The oxidation reaction in the step (vii) is known, and is performed, forexample, by a reaction with the alcohol compound at −78 to 80° C. in asolvent (for example, an organic solvent (for example, chloroform,methylene chloride, ethyl acetate, isopropyl acetate, tetrahydrofuran,dimethylformamide and the like), water, or a mixed solvent of two ormore of them and the like), in the presence of a combination of anactivating agent (for example, a combination of a diimide compound (forexample, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,dicyclohexylcarbodiimide and the like) and an acid (for example,dichloroacetic acid, trifluoroacetic acid, acetic acid and the like), orpyridine sulfur trioxide complex, oxalyl chloride and the like) and anoxidizing agent (for example, dimethyl sulfoxide and the like), or acombination of an activating agent (for example,2,2,6,6-tetramethylpiperidine-1-oxy radical, 2-hydroxy-2-azaadamantaneand the like) and an oxidizing agent (for example, a sodium hypochloriteaqueous solution, trichloroisocyanuric acid and the like) and the like.Here, as the oxidation reaction in the step (vii), it is preferable touse a combination of a combination of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride anddichloroacetic acid, and dimethyl sulfoxide as an oxidizing agent.

In the present invention, the step (viii) means a step of subjecting acompound represented by the general formula (H) obtained in the step(vii) and a compound represented by the general formula (b):

wherein, all symbols represent the same meanings as those describedabove, to a reaction in an organic solvent, or in water, or in a mixedsolution thereof, in the presence of a base, in the presence or absenceof an additive to produce a compound represented by the general formula(I):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof.

Examples of the organic solvent in the step (viii) includetetrahydrofuran (THF), dimethylformamide (DMF), dimethoxyethane (DME),dioxane, acetonitrile, ethanol, methylene chloride, isopropanol and thelike. In the step (viii), a mixed solution of an organic solvent andwater is preferable, and a mixed solution of tetrahydrofuran,isopropanol and water is more preferable.

Examples of the base in the step (viii) include sodium hydride, sodiumhydroxide, potassium hydroxide, potassium phosphate, potassiumtert-butoxide, potassium carbonate, a tertiary amine (for example,triethylamine and the like) and the like, and it is preferable to use acombination of triethylamine and lithium chloride as an additivethereof.

In the present invention, the step (ix) means a step of subjecting acompound represented by the general formula (I) obtained in the step(viii), or a salt thereof to an asymmetric reduction reaction to producea compound represented by the general formula (J):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof.

The asymmetric reduction reaction in the step (ix) is known, and isperformed, for example, in an organic solvent (for example, THF, DME,toluene, methylene chloride, diethyl ether, dioxane and the like), byusing an asymmetric reducing agent (for example,chlorobis(2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)borane and the like),or a combination of a chiral auxiliary and a reducing agent((R)-2-methyl-CBS-oxazaborolidine and a boron hydride-tetrahydrofurancomplex or a borane dimethyl sulfide complex, (S)-(−)-binaphthol andlithium aluminium hydride and the like), at a temperature of −100 to 50°C. Here, toluene is preferable as the organic solvent, andchlorobis(2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)borane is preferableas the asymmetric reducing agent.

In the present invention, the step (x) means a step of subjecting acompound represented by the general formula (J) obtained in the step(ix), or a salt thereof to a deprotection reaction to produce a compoundrepresented by the general formula (K):

wherein, all symbols represent the same meanings as those describedabove.

The deprotection reaction of a hydroxyl group in the step (x) is known,and the deprotection reaction can be performed in the same manner asdescribed in the step (vi).

In the step (x), when T¹ is a p-phenybenzoyl group, the deprotectionreaction under the basic condition performed by using lithiumisopropoxide as the alkoxide of the alkali metal and THF, isopropanol asthe organic solvent is preferable.

The production method according to the present invention includes allmethods for producing the present compound or an arbitrary intermediatecompound for manufacturing the same by carrying out one or two or moreconsecutive steps out of the above steps (i) to (x), but includes inparticular the following production methods.

(1) The method for producing a compound represented by the generalformula (G), or a salt thereof, by using the above-described compoundrepresented by the general formula (A) and sequentially carrying out theabove described step (i)→step (ii)→step (iii)→step (iv)→step (v)→step(vi).(2) The method for producing a compound represented by the generalformula (I), or a salt thereof, by using the above-described compoundrepresented by the general formula (G), or a salt thereof andsequentially carrying out the above described step (vii)→step (viii).(3) The method for producing a compound represented by the generalformula (K) including the present compound, by using the above-describedcompound represented by the general formula (I), or a salt thereof andsequentially carrying out the above described step (ix)→step (x).(4) The method for producing a compound represented by the generalformula (K) including the present compound, by using the above-describedcompound represented by the general formula (A), and sequentiallycarrying out the above described step (i)→step (x).

Here, any of arbitrary intermediate compounds for the manufacturerepresented by the general formulae (B), (C), (G), (I) and (J) may be,if necessary, converted to a salt according to a known method.

In the present invention, a compound represented by the general formula(A), and a compound represented by the general formula (a) or thegeneral formula (b) used as starting raw materials are known, or can beeasily produced by a known method.

In the present invention, T¹ is preferably a p-phenybenzoyl group.

In the present invention, T² is preferably a benzyl group.

In the present invention, it is preferable that T¹ and T² are differentprotecting groups.

In the present invention, the ring 1 is preferably a C3-7 carbocycle,and is more preferably a benzene or cyclohexane ring. Here, thesubstituent of the ring 1 is preferably a C1-4 alkyl group, a C1-4alkoxy group, CF₃, OCF₃ or a halogen atom, and is more preferably a C1-4alkyl group, CF₃, OCF₃ or a halogen atom.

In the present invention, any intermediate which can be produced by eachof the steps is preferable, and a compound represented by the generalformula (B), a compound represented by the general formula (C), acompound represented by the general formula (a), a compound representedby the general formula (D), a compound represented by the generalformula (E), a compound represented by the general formula (F), acompound represented by the general formula (I), and a compoundrepresented by the general formula (J) are more preferable. As acompound represented by the general formula (B),(3aR,4S,5R,6aS)-4-[(benzyloxy)methyl]-2-hydroxyhexahydro-2H-cyclopenta[b]furan-5-yl4-biphenylcarboxylate is preferable. As a compound represented by thegeneral formula (C),(1R,2S,3R,4S)-3-allyl-2-[(benzyloxy)methyl]-4-hydroxycyclopentyl4-biphenylcarboxylate is preferable. As a compound represented by thegeneral formula (a), 2-propanyl 5-(bromomethyl)-5-hexenoate ispreferable. As a compound represented by the general formula (D),(1R,2S,3R,4S)-3-allyl-2-[(benzyloxy)methyl]-4-{[²-methylene-6-oxo-6-(2-propanyloxy)hexyl]oxy}cyclopentyl4-biphenylcarboxylate is preferable. As a compound represented by thegeneral formula (E),(5aR,6S,7R,8aS)-6-[(benzyloxy)methyl]-3-[4-oxo-4-(2-propanyloxy)butyl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate is preferable. As a compound represented by thegeneral formula (F),(3S,5aR,6S,7R,8aS)-6-[(benzyloxy)methyl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate is preferable. As a compound represented by thegeneral formula (I),(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(2,5-difluorophenoxy)-3-oxo-1-buten-1-yl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate is preferable. As a compound represented by thegeneral formula (J),(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate is preferable. In addition, as a compoundrepresented by the general formula (K), 2-propanyl4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoateis preferable.

The production method according to the present invention is not limitedto the above-described present compound, and can be also applied to, forexample, examples described in Patent Literature 1. For example,Examples 16 (1) to 16 (4), Examples 16 (9) to 16 (42), Examples 18 (1)to 18 (4), Example 28, Examples 28 (1) to 28 (17), Example 31, Example40, Example 46, Examples 48 (1) to 48 (2), and Example 97 described inPatent Literature 1 are encompassed in a compound represented by thegeneral formula (K) according to the present invention, and therefore,as apparent to those skilled in the art, the production method accordingto the present invention can be applied to the group of compounds.

In the present invention, unless otherwise indicated, as is apparent tothose skilled in the art, a symbol:

represents that a group is bound to another side of a paper plane (i.e.α-configuration), a symbol:

represents that a group is bound to a front side of a paper plane (i.e.β-configuration), and a symbol:

represents α configuration, β configuration or a mixture thereof at anarbitrary ratio.

In the present invention, a pharmaceutically acceptable salt ispreferable as a salt. Examples of the pharmaceutically acceptable saltinclude a salt of an alkali metal (potassium, sodium and the like), asalt of an alkaline earth metal (calcium, magnesium and the like), anammonium salt, a salt of a pharmaceutically acceptable organic amine(triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine,N-methyl-D-glucamine and the like), an acid adduct salt (an inorganicacid salt (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate,nitrate and the like), an organic acid salt (acetate, trifluoroacetate,lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate,methanesulfonate, ethanesulfonate, benzenesulphonate, toluenesulfonate,isethionate, glucuronate, gluconate and the like) and the like.

EXAMPLES

Hereinafter, the present invention will be described in detail byexamples, but the present invention is not limited thereto.

A solvent in parentheses shown in a place of separation bychromatography and TLC indicates an eluting solvent or a developingsolvent used, and a ratio represents a volumetric ratio.

NMR data are data of ¹H-NMR unless otherwise indicated.

A solvent in measurement is indicated in parentheses shown at a place ofNMR.

A compound name used in the present specification was generally named byusing a computer program, ACD/Name (registered trademark) of AdvancedChemistry Development, which performs naming according to a rule ofIUPAC, or according to IUPAC nomenclature.

Example 1: 2-propanyl5-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-hexenoate

A zinc powder (131 g) was suspended in dimethylacetamide (934 g), and tothe mixture, iodine (28.3 g) was added, and the mixture was stirred atroom temperature. The mixture was heated to 70° C., isopropyl4-bromobutyrate (234 g) (see The Journal of Organic Chemistry, Vol. 70,pages 1227-1236, 2005) was added to the mixture and the mixture waswashed with dimethylacetamide (51 g). After stirring for 2 hours, themixture was cooled to room temperature,[(2-bromo-2-propen-1-yl)oxy](dimethyl)(2-methyl-2-propanyl)silane (168g) (see Organic Letters, Vol. 18, pages 1904-1907, 2016), anddichlorobis(triphenylphosphine)palladium (4.7 g) were added to themixture and a reaction solution was washed with dimethylacetamide (51g). After stirring at 50° C. for 12 hours, the above reaction solutionwas added to a mixture of ammonium chloride (115 g) and water (504 g).Insoluble matters were filtrated through celite, and the residue waswashed with isopropyl acetate (252 g). The filtrate was extracted withmethyl tert-butyl ether (hereinafter abbreviated as MTBE) (65 g),isopropyl acetate (126 g) was added to the organic layer and the organiclayer was washed twice with water (128 g). The organic layer wasconcentrated under reduced pressure to give the title compound (218 g)having the following physical properties.

TLC: Rf 0.60 (hexane:ethyl acetate=9:1);

¹H-NMR (CDCl₃): δ 5.06-5.04, 5.04-4.96, 4.83, 4.06, 2.28, 2.07-2.02,1.82-1.72, 1.23, 0.91, 0.07.

Example 2: 2-propanyl 5-(hydroxymethyl)-5-hexenoate

The compound produced in Example 1 (217 g) was dissolved in isopropanol(282 g), 2 M hydrochloric acid (36 mL) was added to the solution, andthe solution was stirred at room temperature for 3 hours. Water (130 g),sodium hydrogen carbonate (7 g), MTBE (65 g) and heptane (65 g) wereadded to the reaction solution and the liquid mixture was separated. Theorganic layer was washed with water (130 g), and 18% brine (120 g). Theorganic layer was dried over magnesium sulfate, and thereafter, wasfiltrated. The solvent in the filtrate was distilled off, and theresidue was purified by silica gel column chromatography to give thetitle compound (71.8 g) having the following physical properties.

TLC: Rf 0.33 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 5.06-5.04, 5.04-4.94, 4.90-4.88, 4.09, 2.30, 2.11,1.80, 1.53, 1.23.

Example 3: 2-propanyl 5-(bromomethyl)-5-hexenoate

The compound produced in Example 2 (20 g) and triethylamine (13 g) weredissolved in toluene (160 g), and methanesulfonyl chloride (12.9 g) wasadded dropwise to the solution under cooling with ice. After stirringfor 30 minutes, water (50 g) was added to the solution, the liquidmixture was separated, and the organic layer was washed with water (50g) and 18% brine (25 g). The organic layer was dried over magnesiumsulfate, and thereafter, was filtrated to give a filtrate containing2-propanyl 5-{[(methylsulfonyl)oxy]methyl}-5-hexenoate. Lithium bromide(11.2 g) was added to the filtrate, and the mixture was stirred at roomtemperature for 15 hours. Water (50 g) was added to the mixture, theliquid mixture was separated, and the organic layer was washed withwater (30 g) and 18% brine (25 g). The organic layer was dried overmagnesium sulfate, and thereafter, was filtrated. The solvent in thefiltrate was distilled off, and the residue was purified by distillationunder reduced pressure to give the title compound (18.7 g) having thefollowing physical properties.

TLC: Rf 0.52 (hexane:ethyl acetate=6:1);

¹H-NMR (CDCl₃): δ 5.19, 5.05-4.97, 3.96, 2.33-2.23, 1.86-1.75, 1.24.

Example A: 2,2-bis(hydroxymethyl)cyclopentan-1-one

Cyclopentanone (50 g) (CAS Registry Number: 120-92-3) was placed in areaction vessel, the internal temperature was cooled to 5° C. or lower,and potassium carbonate (12.2 g) was added thereto. Subsequently,formalin (28% solution) (119.7 g) was added dropwise over 1 hour at thesame temperature and the mixture was stirred for 2 hours. The reactionsolution was extracted three times with ethyl acetate (250 mL). Theobtained organic layer was dried over magnesium sulfate, and thereafter,concentrated under reduced pressure to give the title compound (21.9 g)having the following physical properties.

¹H-NMR (CDCl₃): δ 4.27-4.19, 2.71-2.59, 1.92-1.83, 1.83-1.71.

Example B: (2-oxocyclopentane-1,1-diyl)bis(methylene) dimethanesulfonate

Ethyl acetate (110 mL) and the compound produced in Example A (21.9 g)were placed in a reaction vessel, the internal temperature was cooled to10° C. or lower, and triethylamine (33.4 g) was added thereto.Subsequently, methanesulfonyl chloride (37.8 g) was added dropwise tothe mixture at the same temperature over 1 hour and the mixture wasstirred for 30 minutes. A solution of sodium hydrogen carbonate (2.2 g)in water (66 mL) was added to the reaction solution, and the mixture wasextracted with ethyl acetate (110 mL). The obtained organic layer waswashed with water, was dried over magnesium sulfate and then wasconcentrated under reduced pressure to give the title compound (39.1 g)having the following physical properties.

¹H-NMR (CDCl₃): δ 4.24, 4.21, 3.93, 3.39, 2.20, 2.09-1.99.

Example C: 2,2-bis(bromomethyl)cyclopentan-1-one

Methyl ethyl ketone (196 mL) and the compound produced in Example B(39.1 g) were placed in a reaction vessel, followed by the addition oflithium bromide (45.8 g), the temperature was raised to an internaltemperature of 80 to 90° C. and the mixture was stirred for 5 hours. Thereaction solution was cooled to room temperature, was washed twice withwater (156 mL), was dried over magnesium sulfate and then wasconcentrated under reduced pressure to give the title compound (29.3 g)having the following physical properties.

¹H-NMR (CDCl₃): δ 3.51, 3.47, 2.38, 2.27, 2.04.

Example 3-1:2-propanyl 5-(bromomethyl)-5-hexenoate

Isopropyl alcohol (146 mL) and the compound produced in Example C (29.2g) were placed in a reaction vessel, and the internal temperature wascooled to 10° C. or lower. Subsequently, a solution of potassiumtert-butoxide (30.3 g) in isopropyl alcohol (292 mL) was added dropwisethereto over 1 hour. The mixture was stirred at the same temperature for30 minutes, acetic acid (13.0 g) was added dropwise to the mixture, andthe mixture was diluted with toluene (204 mL). The reaction solution waswashed with water (146 mL) and a solution of sodium hydrogen carbonate(18.1 g) in water (146 mL), followed by washing twice with water (146mL), the solution was dried over magnesium sulfate and then wasconcentrated under reduced pressure. The obtained residue was distilledunder reduced pressure to give the title compound (25.0 g).

Example D: 2-propanyl 6-hydroxyhexanoate

Isopropyl alcohol (150 mL) was placed in a reaction vessel, the internaltemperature was cooled to 10° C. or lower, and sulfuric acid (0.26 g)was added thereto. Subsequently, a solution of ε-caprolactone (30 g)(CAS Registry Number: 502-44-3) in isopropyl alcohol (150 mL) was addeddropwise thereto at the same temperature over 1 hour and 30 minutes. Asaturated sodium hydrogen carbonate aqueous solution (30 mL) was addedto the reaction solution, and the mixture was concentrated under reducedpressure. The obtained residue was distilled under reduced pressure togive the title compound (26.3 g) having the following physicalproperties.

¹H-NMR (CDCl₃): δ 5.01, 3.63, 2.29, 1.70-1.52, 1.45-1.35, 1.23.

Example E: 2-propanyl 6-oxohexanoate

Dichloromethane (25 mL), water (25 mL) and the compound produced inExample D (5.0 g) were placed in a reaction vessel, and the mixture wascooled to an internal temperature of 5° C. or lower. Subsequently,potassium bromide (45.3 mg), sodium hydrogen carbonate (1.2 g) and2,2,6,6-tetramethylpiperidine 1-oxyl (345.1 mg) were added thereto. Atthe same temperature, a sodium hypochlorite aqueous solution (availablechlorine 4.8%) (153.6 g) was added dropwise thereto over 30 minutes. Theorganic layer in the reaction solution was preparatively isolated andthe aqueous layer was extracted twice with dichloromethane (50 mL). Theobtained organic layers were combined, washed with water (50 mL) andconcentrated under reduced pressure. The obtained residue was distilledunder reduced pressure to give the title compound (2.5 g) having thefollowing physical properties. ¹H-NMR (CDCl₃): δ 9.78, 5.01, 2.54-2.40,2.34-2.24, 2.30, 1.67, 1.23.

Example 2-1:2-propanyl 5-(hydroxymethyl)-5-hexenoate

Isopropyl alcohol (2 mL), the compound produced in Example E (1.0 g),formalin (37% solution) (0.47 g) and diethylamine hydrochloride (63 mg)were placed in a reaction vessel, the internal temperature was raised to50° C., and the mixture was stirred for 1 hour. At the same temperature,diethylamine hydrochloride (573 mg) was added thereto and the mixturewas stirred for 4 hours. The reaction solution was cooled to roomtemperature, water (10 mL) was added to the reaction solution, and themixture was extracted twice with MTBE (10 mL). The obtained organiclayer was washed with water (10 mL) and concentrated under reducedpressure to give a residue containing 2-propanyl 5-formyl-5-hexenoate.THF (1 mL) was added to the residue, and the mixture was cooled to aninternal temperature of 5° C. or lower. At the same temperature, sodiumborohydride (219.4 mg) was added to the mixture, and methanol (1 mL) wasadded dropwise to the mixture. After stirring at the same temperaturefor 30 minutes, water (5 mL) was added to the mixture and the mixturewas extracted three times with ethyl acetate (5 mL). The organic layerswere combined, concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=3:1) to give the title compound (368.1 mg).

Example 3-2:2-propanyl 5-(bromomethyl)-5-hexenoate

Using the compound produced in Example 2-1 instead of the compoundproduced in Example 2, the title compound was obtained by subjecting thecompound to the operation having the same purpose as that of Example 3.

Example 4: (3aR,4S,5R,6aS)-4-[(benzyloxy)methyl]-2-hydroxyhexahydro-2H-cyclopenta[b]furan-5-yl4-biphenylcarboxylate

A solution of (3aR,4S,5R,6aS)-4-[(benzyloxy)methyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl4-phenylbenzoate (70.0 g) (CAS Registry Number: 31752-98-4) (ShanghaiJulong Pharmaceutical R&D Co. Ltd.) in THF (350 mL) was cooled to −65°C. and 1 M isobutylaluminium hydride-toluene solution (190 mL) was addedthereto at −55° C. or lower, and the reaction mixture was washed withTHF (35 mL). The reaction mixture was stirred at −65° C. for 1 hour.Potassium sodium tartrate tetrahydrate (178 g) was dissolved in water(280 mL) in another reaction vessel and ethyl acetate (350 mL) was addedthereto. The above reaction mixture was added to the mixture at 40° C.or lower and the mixture was washed with THF (35 mL). After stirring at30° C. for 1 hour, the liquid mixture was separated. The organic layerwas washed with 20% brine (140 mL), dried over magnesium sulfate, andthen filtrated. The solvent in the filtrate was distilled off, theresidue was suspended in a mixed solution of ethyl acetate (210 mL) andheptane (210 mL), and the suspension was stirred at room temperature for30 minutes. The obtained crystals were collected by filtration andwashed with a mixed solution of ethyl acetate (70 mL) and heptane (70mL). By drying under reduced pressure at 50° C., the title compound(63.7 g) having the following physical properties was obtained.

¹H-NMR (CDCl₃): δ 8.05, 7.65-7.60, 7.49-7.45, 7.41-7.38, 7.32-7.24,5.72, 5.33, 4.80, 4.52, 3.52, 2.78, 2.55, 2.48, 2.35, 2.24, 2.16-2.06.

Example 5:(1R,2S,3R,4S)-3-allyl-2-[(benzyloxy)methyl]-4-hydroxycyclopentyl4-biphenylcarboxylate

Methyltriphenylphosphonium bromide (63.9 g) was added to a solution ofpotassium tert-butoxide (16.3 g) in THF (550 mL) and the mixture waswashed with THF (61 mL). A solution of the compound produced in Example4 (61.4 g) in THF (370 mL) was added to the mixture at −15° C. or lower,and the mixture was stirred for 1 hour. 0.5 M Hydrochloric acid (250 mL)and ethyl acetate (210 mL) were placed in a separate reaction vessel,the above reaction mixture was added thereto at 30° C. or lower and themixture was washed with ethyl acetate (31 mL). The liquid mixture wasseparated, and the organic layer was washed sequentially with 5% sodiumbicarbonate aqueous solution (250 mL) and 20% brine (120 mL). Theorganic layer was dried over magnesium sulfate, and thereafter, wasfiltrated. The solvent in the filtrate was distilled off, and theobtained residue was purified by silica gel column chromatography(heptane:ethyl acetate=8:1). Methanol (490 mL) was added to the obtainedsolid, and the mixture was stirred at 40° C. for 15 minutes. The mixturewas filtrated, and washing with methanol (430 mL) was performed at 40°C. After cooling the filtrate to room temperature, water (61 mL) wasadded thereto. Seed crystals were added to precipitate crystals, andwater (550 mL) was added thereto and the crystals were aged at roomtemperature for 1 hour. The obtained crystals were collected byfiltration and washed with a mixed solution of methanol (180 mL) andwater (120 mL). By drying under reduced pressure at 60° C., the titlecompound (57.1 g) having the following physical properties was obtained.

TLC: Rf 0.50 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 8.09, 7.68-7.60, 7.48-7.44, 7.42-7.37, 7.35-7.24,5.89, 5.41, 5.13, 5.03, 4.58, 4.50, 4.29, 3.75, 3.56, 2.42-2.26,2.02-1.93, 1.69.

Example 6:(1R,2S,3R,4S)-3-allyl-2-[(benzyloxy)methyl]-4-{[2-methylene-6-oxo-6-(2-propanyloxy)hexyl]oxy}cyclopentyl4-biphenylcarboxylate

To a solution of the compound produced in Example 5 (70.0 g) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (hereinafterabbreviated as DMPU) (280 mL), the compound produced in Example 3 (78.8g) (here, the compound produced in Example 3-1 or Example 3-2 may beused) was added and the mixture was washed with DMPU (70 mL). Themixture was cooled to −25° C., a solution of sodium tert-butoxide (38.0g) in DMPU (280 mL) was added thereto and the mixture was stirred for 1hour. 1 M Hydrochloric acid (350 mL) and MTBE (560 mL) were placed in aseparate reaction vessel, the above reaction mixture was added theretoat 30° C. or lower and the mixture was washed with MTBE (70 mL). Theliquid mixture was separated and the aqueous layer was re-extracted withMTBE (350 mL). The organic layers were combined, washed with MTBE (70mL) and washed sequentially with 5% sodium bicarbonate aqueous solution(140 mL) and 20% brine (140 mL). The organic layer was dried overmagnesium sulfate, and thereafter, was filtrated. The solvent in thefiltrate was distilled off, and the obtained residue was purified bysilica gel column chromatography (heptane:ethyl acetate=20:1) to givethe title compound (91.4 g) having the following physical properties.

TLC: Rf 0.47 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 8.09, 7.65-7.61, 7.48-7.37, 7.31-7.25, 5.84, 5.40,5.10-4.87, 4.58, 4.49, 3.96, 3.88, 3.78-3.70, 3.56, 2.46, 2.35,2.26-1.97, 1.76, 1.19.

Example 7:(5aR,6S,7R,8aS)-6-[(benzyloxy)methyl]-3-[4-oxo-4-(2-propanyloxy)butyl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

Umicore M2 (trade name) (513 mg) (CAS registry number: 536724-67-1) wasadded to a toluene (450 mL) solution of the compound produced in Example6 (66.0 g) and the mixture was washed with toluene (13 mL). Afterheating at 80° C. and stirring for 1 hour, the solvent was distilledoff. The obtained residue was purified by silica gel columnchromatography (heptane:ethyl acetate=20:1→10:1) to give the titlecompound (53.6 g) having the following physical properties.

TLC: Rf 0.57 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 8.08, 7.65-7.61, 7.49-7.37, 7.28-7.20, 5.50, 5.19,5.01, 4.50, 4.38, 4.15-4.02, 3.52, 2.75-2.63, 2.37, 2.26, 2.20, 2.04,1.92-1.83, 1.74-1.66, 1.23.

Example 8:(3S,5aR,6S,7R,8aS)-6-[(benzyloxy)methyl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

Bis(cyclooctadiene)iridium(I)tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (3.37 g) (CAS RegistryNumber: 666826-16-0) and(S,S)-(4,5-dihydro-4-isopropyl-2-oxazolyl)-2-[di(1-naphthyl)phosphino]ferrocene(1.77 g) (CAS Registry Number: 950201-43-1) were dissolved in methylenechloride (410 mL), and the solution was stirred at room temperature for30 minutes. A solution of the compound produced in Example 7 (51.4 g) inmethylene chloride (51 mL) was added thereto at room temperature, andthe mixture was washed with methylene chloride (51 mL). After stirringat room temperature for 3 hours under pressurized hydrogen at 5atmospheric pressure, the solvent was distilled off. The obtainedresidue was purified by silica gel column chromatography (heptane:ethylacetate=9:1) to give the title compound (50.1 g) having the followingphysical properties.

TLC: Rf 0.57 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 8.07, 7.65-7.61, 7.49-7.38, 7.24-7.21, 5.17, 5.00,4.49, 4.10-3.99, 3.53, 2.97, 2.69, 2.25, 2.16, 2.04, 1.98-1.76,1.73-1.59, 1.23, 1.19-1.03.

Example 9:(3S,5aR,6S,7R,8aS)-6-(hydroxymethyl)-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

20% Palladium hydroxide on carbon (water content 50%, 1.47 g) was addedto a solution of the compound produced in Example 8 (14.7 g) inisopropyl acetate (74 mL), and the mixture was stirred at roomtemperature for 3 hours under the hydrogen atmosphere at 1 atmosphericpressure. The reaction solution was filtrated, and washing withisopropyl acetate (15 mL) was performed. The solvent in the filtrate wasdistilled off, isopropyl acetate (22 mL) was added to the obtainedresidue, and the mixture was heated to 35° C. for dissolution. Heptane(74 mL) was added to precipitate crystals and the mixture was cooled toroom temperature and the crystals were aged for 30 minutes. The obtainedcrystals were collected by filtration and washed with heptane (29 mL) at0° C. The solvent in the filtrate was distilled off, and the obtainedresidue was purified by silica gel column chromatography (heptane:ethylacetate=3:1), and was combined with the above crystals. MTBE (47.6 g)was added to the obtained compound at 35° C. for dissolution. Heptane(95.2 mL) and seed crystals were added to precipitate crystals. Thecrystals were cooled to 0° C. and aged for 30 minutes. The obtainedcrystals were collected by filtration and washed with heptane (23.8 mL)at 0° C. By drying under reduced pressure at 40° C., the title compound(9.72 g) having the following physical properties was obtained.

TLC: Rf 0.29 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 8.09, 7.67-7.60, 7.46, 7.39, 5.14, 4.99, 4.07-4.01,3.68, 3.57, 2.97, 2.60, 2.55, 2.24, 2.08-1.81, 1.73-1.51, 1.22,1.19-1.01.

Example 10:(3S,5aR,6R,7R,8aS)-6-formyl-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.6 g),isopropyl acetate (240 mL) and dimethyl sulfoxide (250 mL) were added tothe compound produced in Example 9 (49.5 g) and the mixture was cooledto 10° C. Dichloroacetic acid (12.9 g) was added to the mixture at 10°C. or lower, and the mixture was stirred at 10° C. for 2 hours. 1 MHydrochloric acid (250 mL) was placed in a separate reaction vessel andthe above reaction mixture was added thereto at 30° C. or lower. Theliquid mixture was separated, and the organic layer was washedsequentially with 5% sodium bicarbonate aqueous solution (250 mL) and20% brine (250 mL). The organic layer was dried over magnesium sulfate,and thereafter, was filtrated. The solvent in the filtrate was distilledoff, isopropanol (250 mL) was added to the residue, and the mixture washeated to 50° C. for dissolution. The mixture was cooled to 0° C. toprecipitate crystals, and water (250 mL) was added thereto. The crystalswere aged at room temperature for 30 minutes, and the obtained crystalswere collected by filtration. The crystals were washed with a mixedsolution of isopropanol (75 mL) and water (75 mL), and dried underreduced pressure at room temperature to give the title compound (46.3 g)having the following physical properties.

TLC: Rf 0.59 (hexane:acetone=3:2);

¹H-NMR (CDCl₃): δ 9.75, 8.08, 7.67-7.61, 7.47, 7.39, 5.35, 5.00,4.13-4.04, 2.99, 2.81, 2.71, 2.38, 2.25, 2.02, 1.97-1.89, 1.81,1.74-1.53, 1.23, 1.19-1.04.

Example 11:(3S,5aR,6R,7R,8aS)-6-[(1E)-4-(2,5-difluorophenoxy)-3-oxo-1-buten-1-yl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

THF (400 mL), isopropanol (80 mL) and water (20 mL) were mixed toprepare Solution A. Solution A (300 mL) was added to dimethyl[3-(2,5-difluorophenoxy)-2-oxopropyl]phosphonate (41.4 g) (CAS RegistryNumber: 1402924-07-5), and lithium chloride (5.97 g) and triethylamine(14.2 g) were added thereto at 5° C. or lower. A solution (100 mL) ofthe compound produced in Example 10 (46.3 g) in Solution A was addedthereto at 10° C. or lower, and the mixture was washed with Solution A(50 mL). The mixture was stirred at room temperature for 2 hours.Isopropyl acetate (200 mL) and 1 M hydrochloric acid (100 mL) wereplaced in a separate reaction vessel, the above reaction mixture wasadded thereto at 30° C. or lower and the mixture was washed withisopropyl acetate (50 mL). The liquid mixture was separated, and theorganic layer was washed sequentially with 5% sodium bicarbonate aqueoussolution (100 mL) and 20% brine (100 mL). The organic layer was driedover magnesium sulfate and was filtrated. The solvent in the filtratewas distilled off, and the obtained residue was purified by silica gelcolumn chromatography (heptane:isopropyl acetate=85:15→75:25).Isopropanol (855 mL) was added to the obtained compound, and the mixturewas heated to 60° C. for dissolution. The mixture was cooled to 30° C.or lower to precipitate crystals and the crystals were aged for 2 hours.The obtained crystals were collected by filtration and washed withisopropanol (170 mL). By drying under reduced pressure at roomtemperature, the title compound (43.0 g) having the following physicalproperties was obtained.

TLC: Rf 0.55 (hexane:acetone=3:2);

¹H-NMR (CDCl₃): δ 8.04, 7.62, 7.47, 7.40, 7.01-6.92, 6.59-6.55, 6.44,5.09, 5.01, 4.74, 4.11-4.06, 2.97, 2.84, 2.71, 2.25, 2.00-1.47, 1.23,1.20-1.01.

Example 12:(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

Toluene (269 mL) was added tochlorobis(2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)borane (57.6% heptanesolution, 89.5 g) (CAS Registry Number: 85116-37-6), the mixture wascooled to −50° C., a solution of the compound produced in Example 11(42.0 g) in toluene (126 mL) was added thereto at −50° C. and themixture was washed with toluene (42 mL). The mixture was stirred at −50°C. for 5.5 hours, and isopropanol (42 mL) and a solution of2,6-di-tert-butyl-p-cresol (1.40 g) in toluene (8.4 mL) were addedsequentially thereto. After raising the temperature to 0° C., a solutionof phosphoric acid (22.0 g) in water (168 mL) was added to the mixtureat 20° C. or lower. Toluene (84 mL) was added to the mixture, the liquidmixture was separated, and the organic layer was washed sequentiallywith 5% sodium bicarbonate aqueous solution (210 mL) and 20% brine (210mL). The organic layer was dried over magnesium sulfate, and thereafter,was filtrated. The solvent in the filtrate was distilled off, and theobtained residue was purified by silica gel column chromatography(heptane:isopropyl acetate=6:1→2:1) to give the title compound (40.0 g)having the following physical properties.

TLC: Rf 0.31 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 8.07, 7.65-7.60, 7.49-7.45, 7.39, 6.97, 6.64-6.53,5.78, 5.63, 5.08-4.97, 4.51, 4.10-4.03, 3.90, 3.83, 2.97, 2.77, 2.54,2.37, 2.25, 2.02, 1.96-1.45, 1.23, 1.09-1.01.

Example 13: 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

To a suspension of lithium isopropoxide (7.97 g) in isopropanol (240mL), a solution of the compound produced in Example 12 (40.0 g) in THF(120 mL) was added at room temperature and the mixture was washed withTHF (12 mL). After stirring at 45° C. for 3.5 hours, the mixture wascooled to room temperature. 1 M Hydrochloric acid (216 mL) and isopropylacetate (360 mL) were added to the mixture at 30° C. or lower, theliquid mixture was separated, and the organic layer was washedsequentially with 5% sodium bicarbonate aqueous solution (120 mL) and20% brine (120 mL). The organic layer was dried over magnesium sulfate,and thereafter, was filtrated. The solvent in the filtrate was distilledoff, and the obtained residue was purified by silica gel columnchromatography (heptane:isopropyl acetate=40:60→34:66→0:100). Theobtained compound was dissolved in isopropyl acetate (46.3 mL) and themixture was filtrated. Washing twice with isopropyl acetate (4.9 mL) wasperformed. The filtrate was heated to 60° C., and heptane (236 mL) wasadded thereto. The mixture was cooled to 40° C., and seed crystals wereadded to precipitate crystals. Heptane (59 mL) was further added and themixture was cooled to room temperature and the crystals were aged for 1hour. The obtained crystals were collected by filtration and washed witha mixed solution of isopropyl acetate (19.7 mL) and heptane (98.5 mL).By drying under reduced pressure at 45° C., the title compound (16.2 g)having the following physical properties was obtained.

TLC: Rf 0.54 (ethyl acetate);

¹H-NMR (CDCl₃): δ 0.92-1.18, 1.21, 1.34-1.82, 1.82-1.96, 2.03-2.18,2.23, 2.28, 2.41-2.54, 2.78, 2.84-2.98, 3.62-3.80, 3.86-4.11, 4.47-4.61,4.89-5.07, 5.54-5.76, 6.54-6.66, 6.66-6.76, 6.93-7.05.

According to the above Examples, for example, when the starting material(3aR,4S,5R,6aS)-4-[(benzyloxy)methyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl4-phenylbenzoate was 70 g, the total yield of the present compound wasabout 18%. On the other hand, according to the known production method,for example, when the starting material(3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-onewas 20 g, the total yield of the present compound was about 0.058%.Further, the yield of the desired diastereomer in Example 8 of thepresent invention (specifically, in the compound described in Example 8,the compound of which the asymmetric carbon atom at the 3-position(carbon atom to which the a chain in the so-called prostaglandinskeleton is bonded) is in the S configuration) was about 90%, whereas inthe corresponding Example 9→Example 10 of the known production method,the yield of the desired diastereomer was about 60%. Accordingly, it wasrevealed that the total yield of the production method according to thepresent invention is higher than that of the known production method,and the production method according to the present invention can stablysupply the present compound.

INDUSTRIAL APPLICABILITY

According to the present invention, since the total reaction yield ishigh and the present compound can be stably supplied, the presentinvention can be a useful method for producing the present compoundwhich can be used on an industrial production scale.

The invention claimed is:
 1. A method for producing a compoundrepresented by formula (G) or a salt thereof:

wherein, R¹ represents a C1-6 alkyl group optionally substituted with ahydroxyl group or a C1-4 alkoxy group, Z represents (1) —(CH₂)_(m)—, (2)—(CH₂)_(n)—CH═CH—, or (3) —(CH₂)_(p)-A-CH₂—, A represents an oxygenatom, or a sulfur atom, m represents an integer of 1 to 6, n representsan integer of 1 to 4, and p represents an integer of 1 to 4, and T¹represents (1) a p-phenybenzoyl group, (2) a methyl group, (3) a tritylgroup, (4) a methoxymethyl group, (5) a 1-ethoxyethyl group, (6) amethoxyethoxymethyl group, (7) a benzyloxymethyl group, (8) atrimethylsilyl group, (9) a triethylsilyl group, (10) at-butyldimethylsilyl group, (11) a t-butyldiphenylsilyl group, (12) atriisopropylsilyl group, (13) a benzyl group, (14) a p-methoxybenzylgroup, (15) an acetyl group, (16) a pivaloyl group, (17) a benzoylgroup, (18) an allyloxycarbonyl group, (19) a2,2,2-trichloroethoxycarbonyl group, (20) a t-butoxycarbonyl group, (21)an allyl group, or (22) a tosyl group, the method comprising thefollowing steps (i) to (vi): step (i): subjecting a compound representedby formula (A):

wherein, T² represents a benzyl group, and other symbols represent thesame meanings as those described above, to a reduction reaction toproduce a compound represented by formula (B):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof; step (ii): subjecting the compound representedby formula (B) obtained in the step (i) or a salt thereof to a reactionin an organic solvent, in the presence of a base using a Wittig reagentto produce a compound represented by formula (C):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof; step (iii): subjecting the compoundrepresented by the formula (C) obtained in the step (ii) or a saltthereof and a compound represented by formula (a):

wherein, X represents a halogen atom, a tosyloxy (TsO) group, or amesyloxy (MsO) group, and other symbols represent the same meanings asthose described above, to an alkylation reaction to produce a compoundrepresented by formula (D):

wherein, all symbols represent the same meanings as those describedabove; step (iv): subjecting the compound represented by the formula (D)obtained in the step (iii) to a metathesis reaction to produce acompound represented by formula (E):

wherein, all symbols represent the same meanings as those describedabove; step (v): subjecting the compound represented by the formula (E)obtained in the step (iv) to an asymmetric reduction reaction to producea compound represented by formula (F):

wherein, all symbols represent the same meanings as those describedabove; and step (vi): subjecting the compound represented by the formula(F) obtained in the step (v) to a deprotection reaction to produce thecompound represented by the formula (G) or a salt thereof.
 2. A methodfor producing a compound represented by formula (K):

wherein, Y represents —CH₂—, —O— or —S—,

represents a C3-10 carbocycle or a 3- to 10-membered heterocycleoptionally substituted with 1 to 5 substituents selected from the groupconsisting of (1) a halogen atom, (2) CF₃, (3) OCF₃, (4) a C1-4 alkoxygroup, (5) a C1-4 alkyl group, (6) a hydroxyl group, and (7) a nitrilegroup, R¹ represents a C1-6 alkyl group optionally substituted with ahydroxyl group or a C1-4 alkoxy group, Z represents (1) —(CH₂)_(m)—, (2)—(CH₂)_(n)—CH═CH—, or (3) —(CH₂)_(p)-A-CH₂—, A represents an oxygenatom, or a sulfur atom, m represents an integer of 1 to 6, n representsan integer of 1 to 4, and p represents an integer of 1 to 4, the methodcomprising: producing a compound represented by formula (G) or a saltthereof from a compound represented by formula (A) according to steps(i) to (vi):

wherein, T¹ represents (1) a p-phenybenzoyl group, (2) a methyl group,(3) a trityl group, (4) a methoxymethyl group, (5) a 1-ethoxyethylgroup, (6) a methoxyethoxymethyl group, (7) a benzyloxymethyl group, (8)a trimethylsilyl group, (9) a triethylsilyl group, (10) at-butyldimethylsilyl group, (11) a t-butyldiphenylsilyl group, (12) atriisopropylsilyl group, (13) a benzyl group, (14) a p-methoxybenzylgroup, (15) an acetyl group, (16) a pivaloyl group, (17) a benzoylgroup, (18) an allyloxycarbonyl group, (19) a2,2,2-trichloroethoxycarbonyl group, (20) a t-butoxycarbonyl group, (21)an allyl group, or (22) a tosyl group, and other symbols represent thesame meanings as those described above, step (i): subjecting a compoundrepresented by formula (A):

wherein, T² represents a benzyl group, and other symbols represent thesame meanings as those described above, to a reduction reaction toproduce a compound represented by formula (B):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof; step (ii): subjecting the compound representedby formula (B) obtained in the step (i) or a salt thereof to a reactionin an organic solvent, in the presence of a base using a Wittig reagentto produce a compound represented by formula (C):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof; step (iii): subjecting the compoundrepresented by the formula (C) obtained in the step (ii) or a saltthereof and a compound represented by formula (a):

wherein, X represents a halogen atom, a tosyloxy (Ts0) group, or amesyloxy (Ms0) group, and other symbols represent the same meanings asthose described above, to an alkylation reaction to produce a compoundrepresented by formula (D):

wherein, all symbols represent the same meanings as those describedabove; step (iv): subjecting the compound represented by the formula (D)obtained in the step (iii) to a metathesis reaction to produce acompound represented by formula (E):

wherein, all symbols represent the same meanings as those describedabove; step (v): subjecting the compound represented by the formula (E)obtained in the step (iv) to an asymmetric reduction reaction to producea compound represented by formula (F):

wherein, all symbols represent the same meanings as those describedabove; and step (vi): subjecting the compound represented by the formula(F) obtained in the step (v) to a deprotection reaction to produce thecompound represented by the formula (G) or a salt thereof; producing acompound represented by formula (I) or a salt thereof from the compoundrepresented by the formula (G) or a salt thereof according to steps(vii) to (viii):

wherein, all symbols represent the same meanings as those describedabove, step (vii): subjecting a compound represented by formula (G):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof to an oxidation reaction to produce a compoundrepresented by formula (H):

wherein, all symbols represent the same meanings as those describedabove; and step (viii): subjecting the compound represented by theformula (H) obtained in the step (vii) and a compound represented byformula (b):

wherein, R¹⁰¹ represents a C1-6 alkyl group, and other symbols representthe same meanings as those described above, to a reaction in an organicsolvent, in water, or in a mixed solution thereof, in the presence of abase, in the presence or absence of an additive to produce the compoundrepresented by the formula (I) or a salt thereof; and producing thecompound represented by the formula (K) according to steps (ix) to (x):step (ix): subjecting a compound represented by formula (I):

wherein, all symbols represent the same meanings as those describedabove, or a salt thereof, to an asymmetric reduction reaction to producea compound represented by formula (J) or a salt thereof:

wherein all symbols represent the same meanings as those describedabove; and step (x): subjecting the compound represented by the formula(J) or a salt thereof to a deprotection reaction to produce the compoundrepresented by the formula (K).
 3. The method according to claim 1,wherein T¹ is a p-phenybenzoyl group.
 4. The method according to claim2, wherein the compound represented by the formula (K) is 2-propanyl4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate.5. The method according to claim 2, wherein T¹ is a p-phenybenzoylgroup.